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Laminin-induced signaling in tumor cells
Cancer Letters 223 (2005) 1–10 www.elsevier.com/locate/canlet
Mini-review
Laminin-induced signaling in tumor cells Vered Givant-Horwitza,1, Ben Davidsonb, Reuven Reicha,2,* a
Department of Pharmacology, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 91120, Israel b Department of Pathology, The Norwegian Radium Hospital, Montebello, Oslo, Norway Received 28 August 2004; accepted 30 August 2004
Abstract Laminin is the main non-collagenous glycoprotein found in the basement membrane. The various laminin isoforms are involved in many physiological and pathological processes, including cancer dissemination. The interaction of cancer cells with laminin was identified as a key event in tumor invasion and metastasis. Laminin effects are mediated by laminin receptors that are divided into two groups: integrin and non-integrin receptors. Activation of a specific signal transduction pathway in the cell depends on various factors and may be altered when normal tissue becomes neoplastic. Laminin signals via multiple signal transduction pathways involving various components such as G-proteins, intracellular calcium, phospholipase D, mitogen activated protein kinases, phosphatases, focal adhesion kinase, small GTPases of the Rho family, and cytoskeleton components. This review focuses on the role of laminin in tumor progression, its signaling via the non-integrin 67 kDa laminin receptor and via integrins and the reciprocal relations between these receptors in certain tumors. q 2004 Elsevier Ireland Ltd. All rights reserved. Keywords: Laminin; Laminin-receptor; Integrin; Signal transduction
1. Laminin Laminin is the main non-collagenous glycoprotein found in the basement membrane [1]. It is a heterotrimer of three subunits, a, b and g held together by disulphide bonds to form a shape of a cross [2–4]. Five a chains, three b chains and three g
* Corresponding author. Tel.: C972 2 6757 505; fax: C972 2 6758 912. E-mail address: [email protected] (R. Reich). 1 The work of Vered Givant-Horwitz is supported by the Yeshaya Horowitz Fellowship grant. 2 Reuven Reich is affiliated with the David R. Bloom Center of Pharmacy at the Hebrew University.
chains have been identified and by combination they assemble to form over 14 laminin isoforms [5] that have different tissue distributions and development functions [2,4] (Table 1 [5,6]). Laminin is the first basement membrane component appearing during the early stages of embryonic development, and displays a remarkable repertoire of biological functions [6,7]. Laminin is essential for basement membrane assembly [3], promotes cell attachment [3,4,8] and angiogenesis [4,9,10], induces neurite outgrowth [3,11,12], affects gene expression [13–16] and is involved in cell proliferation [4,15], migration [4,17,18] and differentiation [3,6,19]. Biochemical dissection related some of the laminin functions to specific parts of the glycoprotein. It appears that different parts in
0304-3835/$ - see front matter q 2004 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.canlet.2004.08.030
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Table 1 Laminin isoforms Name
Chain composition
Laminin-1 Laminin-2 Laminin-3 Laminin-4 Laminin-5 Laminin-6 Laminin-7 Laminin-8 Laminin-9 Laminin-10 Laminin-11 Laminin-12 Laminin-14 Laminin-15
a1b1g1 a2b1g1 a1b2g1 a2b2g1 a3b3g2 a3b1g1 a3b2g1 a4b1g1 a4b2g1 a5b1g1 a5b2g1 a2b1g3 a4b2g3 a5b2g3
Based on Refs. [5,6].
the molecule have different effects on cells. Some of these parts are cryptic and interact with cells only after cleavage of laminin by proteases [2,4,8]. In vitro, most structural and functional studies have been performed with laminin-1 (a1b1g1), the main component of Matrigel, which is an extract of basement membrane derived from a murine tumor, and its components are identical, both chemically and immunologically, to authentic basement membrane components [4,5]. Laminin-1 appears early during epithelial morphogenesis in most tissues of the embryo, and remains present as a major epithelial laminin in some adult tissues [6]. Data from studies with laminin-1 cannot be applied to all cell types and all laminin isoforms, and until recently, when recombinant laminin domain production began, the difficulty in isolating intact laminin isoforms precluded the studies of biological functions of most laminin isoforms [5].
2. Laminin promotes tumor progression Metastatic spread of cancer continues to be the greatest challenge to cancer cure. At the core of the process lie the changing adhesive preferences of the tumor cells, which determine their interactions with other cells and with the extracellular matrices, mainly in attachment and degradation processes
[3,20,21]. Basement membranes are lost or penetrated by tumor cells during invasion and metastasis, and discontinuities were shown in basement membranes of malignant tumors but not in those of their benign counterparts [22]. Therefore, laminin–cell interaction in tumors is different from that of normal tissue [6]. In general, epithelial tumors display a laminin chain composition similar to that of their tissue of origin [5], but the expression of laminin receptors is altered in cancer [5,23]. The interaction of cancer cells with laminin was identified as a key event in tumor invasion and metastasis [3,4,21,24]. Invading tumor cells attach to laminin and the interaction increases the metastatic potential of tumor cells [3,4]. In tumors, laminin is produced by cells in the extracellular matrix, and by tumor cells [25–27]. Laminin promotes tumor dissemination by several mechanisms. One of the mechanisms by which laminin contributes to the metastatic spread is induction of tumor cell proliferation [4,6]. Laminin-1-adherent cells showed increased proliferative activity and reduced apoptosis in comparison with the laminin-1-non-adherent cells [28]. In addition, it was shown that laminin is chemotactic and haptotactic for tumor cells [17], therefore involved in tumor cell migration [5]. Furthermore, laminin promotes tumor cell invasion by induction of proteases that degrade various components of the extracellular matrix [4]. In certain metastatic cells, but not in normal cells, laminin induces an increase in matrix metalloproteinase-2 (MMP-2) activity [14], which has a key role in invasion and metastasis [29,30]. Indirectly, laminin and more than 20 peptides derived from the glycoprotein contribute to tumor dissemination by promoting angiogenesis [4,5]. The role of the different laminin isoforms in tumor invasion, angiogenesis and metastasis was reviewed by Patarroyo et al. [5]. It was found that laminin peptides have different malignant properties [31]. For example, the YIGSR sequence of the b1 chain in laminin-1 promotes tumor cell attachment and migration, and when injected together with melanoma cells into a mouse, it decreases angiogenesis, tumor growth and metastasis. Another sequence, SIKVAV, of a1 chain increases angiogenesis, tumor growth and metastasis when injected together with melanoma cells into a mouse [4,9,31].
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3. Laminin signaling It appears that laminin activates various signal transduction pathways. It was shown that chemotaxis induced by laminin-1 is sensitive to pertussis toxin, indicating the involvement of pertussis toxin-sensitive G protein in the signals initiating motility to soluble laminin-1. The absence of response to pertussis toxin indicates that a distinct signal transduction pathway may be involved in haptotaxis [17]. It was shown that human osteoclast-like cells selectively recognize laminin isoforms, an event that induces migration and activates Ca2C-mediated signals. The cell lines adhered to laminin-2 but not to laminin-1, and a sharp increase in intracellular Ca2C was detected upon addition of soluble laminin-2 but not laminin-1, due to release from intracellular calcium stores [18]. Another study showed that laminin-1 induced a rapid and transient mRNA expression of c-fos and c-Jun in PC12 cells, and stimulated the DNA binding activity of the complex of these proteins to the AP-1 site. A correlation was found between cell growth, c-fos expression and the ability of cells to attach to laminin [15]. In tumor cells, laminin-1 results in a time- and dose-dependent activation of phospholipase D (PLD) followed by generation of phosphatidic acid that is involved in signal transduction events leading to the induction of MMP-2 and enhanced invasiveness of metastatic tumor cells [14]. Laminin signaling has been shown to involve kinase/phosphatase cascades since bound laminin induces protein dephosphorylation in neural cells during process formation [11]. A recent study performed in our laboratory showed that mitogen activated protein kinases (MAPK) are involved in laminin signaling [32]. MAPK cascades transduce a diverse spectrum of extracellular and intracellular stimuli into alterations in gene expression and cellular function. The three major mammalian MAPK subgroups include extracellular signal-regulated kinases (ERKs), c-Jun NH2-terminal protein kinase/stress-activated protein kinase (JNKs/ SAPKs) and p38 MAPK [33,34]. We demonstrated that addition of exogenous soluble laminin-1 results in a significant decrease in the phosphorylation (activation) of ERK, JNK and p38 after 30 min of incubation. This laminin-induced dephosphorylation of all MAPK was dose-dependent and transient, as the effect was not seen with other incubation times [32].
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Another study demonstrated that incubation of macrophages with a peptide from the laminin-a1 chain, but not intact laminin-1, triggers protein kinase C-dependent activation of ERK1/2, leading to up-regulation of proteinase expression [35]. These studies suggest that laminin, as an intact glycoprotein, may be involved in signal transduction pathways different than its cleavage products. In addition, various signal transduction pathways may be activated by different laminin receptors.
4. Laminin receptors The biological effects of laminin are mediated by laminin receptors that are divided into two major groups: integrin and non-integrin receptors (Table 2) [5,21,36–39]. Insufficient data exist regarding the roles of both families of receptors in mediating the various effects of laminin [2,23]. 4.1. 67 kDa laminin receptor The 67 kDa laminin receptor is a non-integrin receptor [21]. A highly conserved 37 kDa protein is the precursor of the receptor [40,41], but the exact manner by which it configures its mature form is not Table 2 Laminin receptors and their additional ligands Receptor Integrins
Ligands a1b1 a2b1 a3b1
a6b1 a6b4 a7b1 67 kDa laminin receptor Dystroglycan Heparan sulphate
Collagen (I, II, IV), laminin (1, 2) Collagen (I, II, IV), laminin (1, 2), chondroadherin Fibronectin, collagen (I), laminin (2, 5, 8, 10, 11), nidogen, epiligrin, perlecan Laminin (1, 2, 5, 8, 10, 11) Laminin (1, 2, 5, 10) Laminin (1, 2, 8, 10) Laminina Laminin (1, 2), agrin, perlecan Laminin (1, 2), collagen XVIII
Based on Refs. [5,21,36–39]; laminin-4 receptor interactions presumed to be similar to those of laminin-2. a Most studies on laminin-1.
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clear. It was suggested that acylation followed by homo- or heterodimerization of the acylated 37 kDa precursor, by non-covalent bonds, forms the mature 67 kDa laminin receptor [41,42]. The amino acid sequence of the 37 kDa precursor is extremely well conserved through evolution and corresponds to that of additional proteins, suggesting a multifunctional protein [21,43]. The cDNA of the 37 kDa precursor is virtually identical to a cDNA encoding the ribosomal protein p40, suggesting that the protein is a component of the translational machinery [43]. In addition, the 37 kDa precursor acts as a receptor for cellular prion protein and involved in the life cycle of prions [44,45]. It has also been found that the 37 kDa precursor is identical to the oncofetal antigen protein that is expressed by tumors [46]. Two laminin binding sites were identified on the 67 kDa laminin receptor [21]. The first is called G peptide (amino acids 161–180) [47–49], and the second is at the carboxy terminal (amino acids 205–229), and binds to the peptide YIGSR on b1 chain of laminin [50,51]. The 67 kDa laminin receptor therefore recognizes various binding sites on laminin that are different from the sites recognized by integrins [21,48,50,52], allowing for higher overall binding affinity, but also a range of binding and signaling options. 4.1.1. Physiological and pathological roles The 67 kDa laminin receptor mediates cell attachment to laminin [21,53]. Co-localization of the 67 kDa laminin receptor with the cytoskeleton constituents alpha-actinin and vinculin [54] and the focal adhesion plaque [55] was found. The receptor is involved in several physiological processes such as implantation [56], invasive phenotype of trophoblastic tissue [57], angiogenesis [58,59], T-cell biology [52] and shear stress-dependent endothelial nitric oxide synthase expression [51]. 67 kDa laminin receptor expression is decreased during cell differentiation [21,23,60]. Cell contact expression inhibition [59] and p53-dependent down-regulation [61] were also reported. Increased expression of the 67 kDa laminin receptor correlates with cell proliferation [58], migration [62] and invasion capacity [57]. Clinical data suggest a correlation between 67 kDa laminin receptor expression in tumor cells and tumor progression. Expression of the receptor has been
shown to be up-regulated in neoplastic cells compared to their normal counterparts and directly correlates with an enhanced invasive and metastatic potential in numerous malignancies [23,63–65]. The receptor has been implicated in laminin-induced tumor cell attachment [52,63,66] and migration [67], as well as in tumor angiogenesis [68], growth, invasion and metastasis [21,63,66]. 4.1.2. 67 kDa laminin receptor signaling Studies of laminin-induced signal transduction have focused on integrins [5,69,70] and provided only limited data regarding the role of the 67 kDa laminin receptor in signaling. It was shown that a YIGSR-containing peptide and an anti-67 kDa laminin receptor antibody induce a similar pattern of tyrosine phosphorylation of currently unidentified proteins with a molecular mass ranging from 115 to 130 kDa and an additional heterogeneous protein group of 32 kDa [16]. Although the 67 kDa laminin receptor binds YIGSR [50,51], other laminin-binding sites exit on the receptor [48,52], and displacement and cross-linking studies showed that other proteins may bind the YIGSR peptide [16]. A recent study in our laboratory focused on the role of the 67 kDa laminin receptor in laminin signaling, using cells expressing different levels of the receptor [32]. By stable transfection of A375SM melanoma cells, we established lines expressing reduced or elevated 67 kDa laminin receptor. The antisensetransfected cells that expressed reduced 67 kDa laminin receptor demonstrated significantly less aggressive tumor phenotype, as reflected by their reduced invasiveness through Matrigel, diminished attachment to laminin and decreased MMP-2 expression and activity [32]. We subsequently analyzed the involvement of the mitogen-activated protein kinases (MAPK) and dual specificity phosphatases (DUSP) in 67 kDa laminin receptor signaling [32]. MAPK are activated by phosphorylation of tyrosine and threonine in the activation loop and can be inactivated by serine/ threonine phosphatases, tyrosine phosphatases and DUSPs [33,71,72]. We found that the basal phosphorylation extent (activity) of ERK, JNK and p38 was significantly higher in cell lines expressing reduced 67 kDa laminin receptor, compared to parental cells and sense-transfected cells, regardless
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of the exposure to exogenous laminin-1. The addition of exogenous soluble laminin-1 resulted in an additional transient significant decrease in the phosphorylation of ERK, JNK and p38. This soluble laminin-induced dephosphorylation of all MAPK was independent of the 67 kDa laminin receptor level, since it was seen in all cell lines irrespective of the expression level of the receptor. These findings suggest that the 67 kDa laminin receptor induces prolonged dephosphorylation of ERK, JNK and p38, and that additional exogenous soluble laminin-1 induces further temporary dephosphorylation, apparently not via the 67 kDa laminin receptor. Further study focused on the DUSPs, MKP-1, PAC-1, MKP-4 and MKP-5, which were found to be expressed by the human A375SM melanoma cell line. We found that the increase in MAPK phosphorylation in cells expressing reduced 67 kDa laminin receptor is accompanied by a significant reduction in MKP-1 mRNA level and a significant increase in PAC-1 mRNA level, with no change in MKP-4 and MKP-5 mRNA levels [32]. Since prolonged activation of MAPK results in translocation of the activated kinases into the nucleus [33,71], and since MKP-1 and PAC-1 are nuclear enzymes that are regulated on the transcriptional level [71–74], it is reasonable to speculate that the increase that was seen in the phosphorylation of these MAPK in cells expressing reduced 67 kDa laminin receptor is related to decreased activity of MKP-1 [32]. The increase in PAC-1 mRNA level that accompanied the increase in the phosphorylation of ERK, JNK and p38 in cells expressing reduced 67 kDa laminin receptor can be explained as a negative feedback mechanism, since it has been shown that an increase in ERK phosphorylation results in transcription followed by increased activity of PAC-1, that in turn dephosphorylates and inactivates ERK [74,75]. In summary, the 67 kDa laminin receptor induces down-regulation of MKP-1 expression, that may contribute to the reduced activity (dephosphorylation) of MAPK induced by the receptor, that is followed by an upregulation of PAC-1 expression, as a negative feedback [32]. Interestingly, lower MAPK activity induced by the 67 kDa laminin receptor in our in vitro model, which was characteristic of aggressive phenotype of the tumor cells [32], correlates with our results in a study of clinical specimens from ovarian carcinoma patients.
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We found that increased level and activity of all three MAPK families in ovarian carcinoma cells in effusions is associated with clinical parameters of improved outcome and significantly longer overall survival [76]. 4.2. Integrins Integrins are a large family of cell receptors for extracellular matrix proteins and ligands on other cells (Table 2). Integrins are heterodimeric combination of various a-subunits with various b-subunits [2,39]. By having multiple integrins as receptors for common extracellular matrix proteins, cells have the flexibility to interact with different affinities at the same ligand site and at different sites within the same ligand. The ligand specificity for different integrins can be altered depending on the type of divalent cation present, the surrounding lipid environment and various cellspecific factors. Inside the cell, the short cytoplasmic domains of integrins associate with various cytoskeletal proteins that mediate integrin signal transduction [39]. At least eight integrins bind laminin; some of them bind additional extracellular matrix components as well, and cellular response depends on the sum of integrin–extracellular matrix interactions [2]. Integrins recognize mainly laminin a chains and hence determine cell adhesion and response to laminin isoforms. Although some functions may be common to all laminin variants, others may be unique and isoform-specific, depending on the tissue or organ in which they are abundant [5]. 4.2.1. Integrin signaling Although, it is clear that integrins transduce signals across the plasma membrane that affect gene expression, limited data exist regarding the specific signal transduction pathways activated by specific ligands [39,69]. There are two types of integrin-related signal transduction. The first is direct signaling, where stimulation of integrins by extracellular proteins triggers intracellular signaling events. The second is integrin modulation of mitogen signaling; in this case, integrin-mediated cell anchorage influences signaling pathways activated by growth factors [70]. In general, integrin direct signaling activates focal adhesion kinase (FAK), small GTPases of the Rho family,
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and MAPK [70,77,78], resulting in accumulation of highly phosphorylated proteins and cytoskeletal molecules at adhesion sites [79,80]. Integrin clustering causes activation and autophosphorylation of FAK, which is a cytoplasmic tyrosine kinase. Tyrosine-phosphorylated FAK can recruit Src-family kinases to focal contact sites. This sets up additional tyrosine phosphorylation of proteins such as cytoskeletal proteins and adaptor proteins such as Grb2 [70,78,81]. Small GTPases of the Rho family (Rho, Rac and Cdc42) are involved in integrin signal transduction and affect cytoskeleton arrangement. Rho contributes to cell adhesion to extracellular matrix. Rac and Cdc42, via phosphoinositide 3 kinase (PI3K), mediate the increase in cell motility and invasiveness induced by the integrin [82,83]. Some integrins activate MAPK cascades [80,84]. For example, laminin binding to the integrin a6b4 results in activation of an associated kinase and consequently tyrosine phosphorylation of the b4 subunit cytoplasmic domain, followed by association of the adaptor protein Shc with tyrosine phosphorylated b4 integrin subunit. Shc is then phosphorylated on tyrosine residues, presumably by an integrin-associated kinase, and combines with the adaptor protein Grb2, which exists in a complex with the ras GTP exchange factor SOS. This leads to Ras activation followed by activation of a kinase cascade consisting of Raf, MEK (MAPK/ERK kinase) and ERK, resulting in increased cell motility and proliferation [69,84]. In addition, integrin a6b4 activates the JNK cascade, via Rac1, resulting in jun protein expression. Jun associates with fos, whose expression is induced by ERK cascade, to form the AP-1 transcription factor [84]. In human hepatocellular carcinoma cells, laminin-binding integrin a6b1 stimulation resulted in FAK tyrosine phosphorylation, leading to FAK-GRB2 association and ERK cascade activation, which promotes tumor cell migration [85]. Interestingly, aggregation of integrin receptors, even in the absence of ligand occupancy, is sufficient to induce a prompt trans-membrane accumulation of at least 20 signal transduction molecules, including Src, Rho, Rac1, Ras, Erk1/2 and JNK. Thus, integrin aggregation with or without ligand occupancy triggers activation of both ERK and JNK cascades [80].
4.3. 67 kDa laminin receptor and integrins Integrins and the 67 kDa laminin receptor act together in transducing laminin effects. Limited data exist regarding the roles of the different receptors in mediating specific laminin effects. There are studies that indicate an association between the 67 kDa laminin receptor and the a6 integrin subunit, that is a part of the laminin-binding integrins a6b4 and a6b1 [21,23]. It was found that activation of human T lymphocytes induces an increase in both 67 kDa laminin receptor and a6b1 integrin expression, and that the two receptors mediate avid cellular adherence to laminin [52]. The 67 kDa laminin receptor and the a6b1 integrin were shown to be co-expressed and co-regulated in small-cell lung carcinoma cell lines, and their expression correlated with ability to adhere to laminin [86]. An additional study showed increased expression of the a6 integrin subunit and of the 67 kDa laminin receptor in pancreatic adenocarcinoma specimens, compared with normal pancreatic tissue from the same patient, indicating co-regulation of the receptors [87]. As opposed to the above report, differential expression of the a6 integrin subunit and the 67 kDa laminin receptor was seen in human hepatocellular carcinoma. Although higher expression of both the a6 integrin subunit and the 67 kDa laminin receptor was found in tumor specimens compared to normal tissues from the same patient, the increase in a6 integrin subunit expression was more pronounced than that of the 67 kDa laminin receptor, indicating different regulation of receptor expression [88]. An in vitro study found co-regulation and physical association of the a6 integrin subunit and the 67 kDa laminin receptor. Following incubation of a human vulvar epidermoid carcinoma cell line with laminin for different time periods, the regulation of the 67 kDa laminin receptor correlated with expression of the a6 integrin subunit but not with the expression of other laminin receptors, and cytokine treatment resulted in a reduction in the expression of these two receptors [24]. Specific reduction of the a6 integrin subunit by an antisense was accompanied by a proportional decrease in the cell surface expression of the 67 kDa laminin receptor. Biochemical analyses indicated co-immunoprecipitation of 67 kDa laminin receptor and a6 integrin subunit [24]. Integrins bind laminin at
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different sites than the 67 kDa laminin receptor, which may lead to higher laminin-binding affinity. Some investigators suggested that the 67 kDa laminin receptor is just a co-factor for laminin–integrin interactions [21,24,48], but other reports indicate that the 67 kDa laminin receptor may have additional functions [44,88]. The 67 kDa laminin receptor does not co-localize with a6 integrin subunit in neuroblastoma cell line [44]. Results from an in vitro study and analysis of clinical specimens in our laboratory are in agreement with the hypothesis that the 67 kDa laminin receptor is not merely a co-factor for laminin– integrin interactions. We found that A375SM melanoma cells express two alternatively spliced isoforms of the a6 integrin subunit, a6A and a6B. However, cells expressing reduced 67 kDa laminin receptor showed a significantly reduced mRNA level of the a6B integrin subunit isoform, with no significant change in a6A isoform mRNA level. Thus, the a6B is the important isoform in the concept of co-regulation with the 67 kDa laminin receptor in the A375SM melanoma cell line [32]. Our study of clinical material analyzed the expression of the 67 kDa laminin receptor and the a6 integrin subunit, in effusions and solid tumors of patients diagnosed with serous ovarian carcinoma, and analyzed their predictive roles. 67 kDa laminin receptor mRNA and protein expression was found to be independent of that of the a6 integrin subunit in both solid tumors and effusions of serous ovarian carcinoma. Expression of the 67 kDa laminin receptor was detected in the majority of specimens, at all anatomic sites, and did not correlate with clinico-pathological parameters or survival. In contrast, loss of a6 integrin subunit expression predicted better overall survival [89]. Malignant mesothelioma (MM) is one of the most aggressive human cancers, with a median survival of 8 months if untreated, and up to 2 years in recent series, when surgery was combined with adjuvant therapy [90]. With the exception of brain tumors, such as Glioblastoma Multiforme, that are confined to the central nervous system by anatomic structures, no tumor is less susceptible to clinically detectable distant metastasis and still is associated with these mortality figures. This despite the fact that MM is clearly capable of local invasion and displays the integrin profile needed in order to mediate attachment to all major extracellular matrix proteins [91,92].
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In a recent study, frequent mRNA, but only rare protein expression of the 67 kDa laminin receptor was seen in clinical specimens of MM (Reich et al., submitted for publication). In contrast, expression of this receptor was seen in the majority of breast and lung carcinomas, tumors with high metastatic potential, in addition to the above-described ovarian carcinomas (Reich et al., submitted for publication). These findings suggest that the differences between MM and carcinomas regarding expression of the 67 kDa laminin receptor may account at least in part for the reduced ability of MM to metastasize to distant organs, due to lack of the signaling mediated by the receptor. Local invasion and the less frequent distant metastasis in MM may be mediated by the a6 integrin laminin receptor rather than the non-integrin 67 kDa laminin receptor. Our recent finding that MM shows significantly higher expression of the a6 integrin subunit compared to ovarian and breast carcinomas using flow cytometry (Sigstad et al., submitted for publication) supports this hypothesis.
5. Summary The interaction of cancer cells with laminin is a key-event in tumor invasion and metastasis. Laminin effects are mediated by laminin receptors, and receptor expression is altered in cancer. Activation of a specific signal transduction pathway in the cell depends on the laminin isoforms the cell binds to, the conformation of the glycoprotein, the duration of exposure to laminin and the expression pattern of the different laminin receptors. All the above factors may be altered when normal tissue becomes neoplastic, resulting in various laminin mediated signaling that promote tumor dissemination.
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Mini-review
Laminin-induced signaling in tumor cells Vered Givant-Horwitza,1, Ben Davidsonb, Reuven Reicha,2,* a
Department of Pharmacology, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 91120, Israel b Department of Pathology, The Norwegian Radium Hospital, Montebello, Oslo, Norway Received 28 August 2004; accepted 30 August 2004
Abstract Laminin is the main non-collagenous glycoprotein found in the basement membrane. The various laminin isoforms are involved in many physiological and pathological processes, including cancer dissemination. The interaction of cancer cells with laminin was identified as a key event in tumor invasion and metastasis. Laminin effects are mediated by laminin receptors that are divided into two groups: integrin and non-integrin receptors. Activation of a specific signal transduction pathway in the cell depends on various factors and may be altered when normal tissue becomes neoplastic. Laminin signals via multiple signal transduction pathways involving various components such as G-proteins, intracellular calcium, phospholipase D, mitogen activated protein kinases, phosphatases, focal adhesion kinase, small GTPases of the Rho family, and cytoskeleton components. This review focuses on the role of laminin in tumor progression, its signaling via the non-integrin 67 kDa laminin receptor and via integrins and the reciprocal relations between these receptors in certain tumors. q 2004 Elsevier Ireland Ltd. All rights reserved. Keywords: Laminin; Laminin-receptor; Integrin; Signal transduction
1. Laminin Laminin is the main non-collagenous glycoprotein found in the basement membrane [1]. It is a heterotrimer of three subunits, a, b and g held together by disulphide bonds to form a shape of a cross [2–4]. Five a chains, three b chains and three g
* Corresponding author. Tel.: C972 2 6757 505; fax: C972 2 6758 912. E-mail address: [email protected] (R. Reich). 1 The work of Vered Givant-Horwitz is supported by the Yeshaya Horowitz Fellowship grant. 2 Reuven Reich is affiliated with the David R. Bloom Center of Pharmacy at the Hebrew University.
chains have been identified and by combination they assemble to form over 14 laminin isoforms [5] that have different tissue distributions and development functions [2,4] (Table 1 [5,6]). Laminin is the first basement membrane component appearing during the early stages of embryonic development, and displays a remarkable repertoire of biological functions [6,7]. Laminin is essential for basement membrane assembly [3], promotes cell attachment [3,4,8] and angiogenesis [4,9,10], induces neurite outgrowth [3,11,12], affects gene expression [13–16] and is involved in cell proliferation [4,15], migration [4,17,18] and differentiation [3,6,19]. Biochemical dissection related some of the laminin functions to specific parts of the glycoprotein. It appears that different parts in
0304-3835/$ - see front matter q 2004 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.canlet.2004.08.030
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Table 1 Laminin isoforms Name
Chain composition
Laminin-1 Laminin-2 Laminin-3 Laminin-4 Laminin-5 Laminin-6 Laminin-7 Laminin-8 Laminin-9 Laminin-10 Laminin-11 Laminin-12 Laminin-14 Laminin-15
a1b1g1 a2b1g1 a1b2g1 a2b2g1 a3b3g2 a3b1g1 a3b2g1 a4b1g1 a4b2g1 a5b1g1 a5b2g1 a2b1g3 a4b2g3 a5b2g3
Based on Refs. [5,6].
the molecule have different effects on cells. Some of these parts are cryptic and interact with cells only after cleavage of laminin by proteases [2,4,8]. In vitro, most structural and functional studies have been performed with laminin-1 (a1b1g1), the main component of Matrigel, which is an extract of basement membrane derived from a murine tumor, and its components are identical, both chemically and immunologically, to authentic basement membrane components [4,5]. Laminin-1 appears early during epithelial morphogenesis in most tissues of the embryo, and remains present as a major epithelial laminin in some adult tissues [6]. Data from studies with laminin-1 cannot be applied to all cell types and all laminin isoforms, and until recently, when recombinant laminin domain production began, the difficulty in isolating intact laminin isoforms precluded the studies of biological functions of most laminin isoforms [5].
2. Laminin promotes tumor progression Metastatic spread of cancer continues to be the greatest challenge to cancer cure. At the core of the process lie the changing adhesive preferences of the tumor cells, which determine their interactions with other cells and with the extracellular matrices, mainly in attachment and degradation processes
[3,20,21]. Basement membranes are lost or penetrated by tumor cells during invasion and metastasis, and discontinuities were shown in basement membranes of malignant tumors but not in those of their benign counterparts [22]. Therefore, laminin–cell interaction in tumors is different from that of normal tissue [6]. In general, epithelial tumors display a laminin chain composition similar to that of their tissue of origin [5], but the expression of laminin receptors is altered in cancer [5,23]. The interaction of cancer cells with laminin was identified as a key event in tumor invasion and metastasis [3,4,21,24]. Invading tumor cells attach to laminin and the interaction increases the metastatic potential of tumor cells [3,4]. In tumors, laminin is produced by cells in the extracellular matrix, and by tumor cells [25–27]. Laminin promotes tumor dissemination by several mechanisms. One of the mechanisms by which laminin contributes to the metastatic spread is induction of tumor cell proliferation [4,6]. Laminin-1-adherent cells showed increased proliferative activity and reduced apoptosis in comparison with the laminin-1-non-adherent cells [28]. In addition, it was shown that laminin is chemotactic and haptotactic for tumor cells [17], therefore involved in tumor cell migration [5]. Furthermore, laminin promotes tumor cell invasion by induction of proteases that degrade various components of the extracellular matrix [4]. In certain metastatic cells, but not in normal cells, laminin induces an increase in matrix metalloproteinase-2 (MMP-2) activity [14], which has a key role in invasion and metastasis [29,30]. Indirectly, laminin and more than 20 peptides derived from the glycoprotein contribute to tumor dissemination by promoting angiogenesis [4,5]. The role of the different laminin isoforms in tumor invasion, angiogenesis and metastasis was reviewed by Patarroyo et al. [5]. It was found that laminin peptides have different malignant properties [31]. For example, the YIGSR sequence of the b1 chain in laminin-1 promotes tumor cell attachment and migration, and when injected together with melanoma cells into a mouse, it decreases angiogenesis, tumor growth and metastasis. Another sequence, SIKVAV, of a1 chain increases angiogenesis, tumor growth and metastasis when injected together with melanoma cells into a mouse [4,9,31].
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3. Laminin signaling It appears that laminin activates various signal transduction pathways. It was shown that chemotaxis induced by laminin-1 is sensitive to pertussis toxin, indicating the involvement of pertussis toxin-sensitive G protein in the signals initiating motility to soluble laminin-1. The absence of response to pertussis toxin indicates that a distinct signal transduction pathway may be involved in haptotaxis [17]. It was shown that human osteoclast-like cells selectively recognize laminin isoforms, an event that induces migration and activates Ca2C-mediated signals. The cell lines adhered to laminin-2 but not to laminin-1, and a sharp increase in intracellular Ca2C was detected upon addition of soluble laminin-2 but not laminin-1, due to release from intracellular calcium stores [18]. Another study showed that laminin-1 induced a rapid and transient mRNA expression of c-fos and c-Jun in PC12 cells, and stimulated the DNA binding activity of the complex of these proteins to the AP-1 site. A correlation was found between cell growth, c-fos expression and the ability of cells to attach to laminin [15]. In tumor cells, laminin-1 results in a time- and dose-dependent activation of phospholipase D (PLD) followed by generation of phosphatidic acid that is involved in signal transduction events leading to the induction of MMP-2 and enhanced invasiveness of metastatic tumor cells [14]. Laminin signaling has been shown to involve kinase/phosphatase cascades since bound laminin induces protein dephosphorylation in neural cells during process formation [11]. A recent study performed in our laboratory showed that mitogen activated protein kinases (MAPK) are involved in laminin signaling [32]. MAPK cascades transduce a diverse spectrum of extracellular and intracellular stimuli into alterations in gene expression and cellular function. The three major mammalian MAPK subgroups include extracellular signal-regulated kinases (ERKs), c-Jun NH2-terminal protein kinase/stress-activated protein kinase (JNKs/ SAPKs) and p38 MAPK [33,34]. We demonstrated that addition of exogenous soluble laminin-1 results in a significant decrease in the phosphorylation (activation) of ERK, JNK and p38 after 30 min of incubation. This laminin-induced dephosphorylation of all MAPK was dose-dependent and transient, as the effect was not seen with other incubation times [32].
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Another study demonstrated that incubation of macrophages with a peptide from the laminin-a1 chain, but not intact laminin-1, triggers protein kinase C-dependent activation of ERK1/2, leading to up-regulation of proteinase expression [35]. These studies suggest that laminin, as an intact glycoprotein, may be involved in signal transduction pathways different than its cleavage products. In addition, various signal transduction pathways may be activated by different laminin receptors.
4. Laminin receptors The biological effects of laminin are mediated by laminin receptors that are divided into two major groups: integrin and non-integrin receptors (Table 2) [5,21,36–39]. Insufficient data exist regarding the roles of both families of receptors in mediating the various effects of laminin [2,23]. 4.1. 67 kDa laminin receptor The 67 kDa laminin receptor is a non-integrin receptor [21]. A highly conserved 37 kDa protein is the precursor of the receptor [40,41], but the exact manner by which it configures its mature form is not Table 2 Laminin receptors and their additional ligands Receptor Integrins
Ligands a1b1 a2b1 a3b1
a6b1 a6b4 a7b1 67 kDa laminin receptor Dystroglycan Heparan sulphate
Collagen (I, II, IV), laminin (1, 2) Collagen (I, II, IV), laminin (1, 2), chondroadherin Fibronectin, collagen (I), laminin (2, 5, 8, 10, 11), nidogen, epiligrin, perlecan Laminin (1, 2, 5, 8, 10, 11) Laminin (1, 2, 5, 10) Laminin (1, 2, 8, 10) Laminina Laminin (1, 2), agrin, perlecan Laminin (1, 2), collagen XVIII
Based on Refs. [5,21,36–39]; laminin-4 receptor interactions presumed to be similar to those of laminin-2. a Most studies on laminin-1.
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clear. It was suggested that acylation followed by homo- or heterodimerization of the acylated 37 kDa precursor, by non-covalent bonds, forms the mature 67 kDa laminin receptor [41,42]. The amino acid sequence of the 37 kDa precursor is extremely well conserved through evolution and corresponds to that of additional proteins, suggesting a multifunctional protein [21,43]. The cDNA of the 37 kDa precursor is virtually identical to a cDNA encoding the ribosomal protein p40, suggesting that the protein is a component of the translational machinery [43]. In addition, the 37 kDa precursor acts as a receptor for cellular prion protein and involved in the life cycle of prions [44,45]. It has also been found that the 37 kDa precursor is identical to the oncofetal antigen protein that is expressed by tumors [46]. Two laminin binding sites were identified on the 67 kDa laminin receptor [21]. The first is called G peptide (amino acids 161–180) [47–49], and the second is at the carboxy terminal (amino acids 205–229), and binds to the peptide YIGSR on b1 chain of laminin [50,51]. The 67 kDa laminin receptor therefore recognizes various binding sites on laminin that are different from the sites recognized by integrins [21,48,50,52], allowing for higher overall binding affinity, but also a range of binding and signaling options. 4.1.1. Physiological and pathological roles The 67 kDa laminin receptor mediates cell attachment to laminin [21,53]. Co-localization of the 67 kDa laminin receptor with the cytoskeleton constituents alpha-actinin and vinculin [54] and the focal adhesion plaque [55] was found. The receptor is involved in several physiological processes such as implantation [56], invasive phenotype of trophoblastic tissue [57], angiogenesis [58,59], T-cell biology [52] and shear stress-dependent endothelial nitric oxide synthase expression [51]. 67 kDa laminin receptor expression is decreased during cell differentiation [21,23,60]. Cell contact expression inhibition [59] and p53-dependent down-regulation [61] were also reported. Increased expression of the 67 kDa laminin receptor correlates with cell proliferation [58], migration [62] and invasion capacity [57]. Clinical data suggest a correlation between 67 kDa laminin receptor expression in tumor cells and tumor progression. Expression of the receptor has been
shown to be up-regulated in neoplastic cells compared to their normal counterparts and directly correlates with an enhanced invasive and metastatic potential in numerous malignancies [23,63–65]. The receptor has been implicated in laminin-induced tumor cell attachment [52,63,66] and migration [67], as well as in tumor angiogenesis [68], growth, invasion and metastasis [21,63,66]. 4.1.2. 67 kDa laminin receptor signaling Studies of laminin-induced signal transduction have focused on integrins [5,69,70] and provided only limited data regarding the role of the 67 kDa laminin receptor in signaling. It was shown that a YIGSR-containing peptide and an anti-67 kDa laminin receptor antibody induce a similar pattern of tyrosine phosphorylation of currently unidentified proteins with a molecular mass ranging from 115 to 130 kDa and an additional heterogeneous protein group of 32 kDa [16]. Although the 67 kDa laminin receptor binds YIGSR [50,51], other laminin-binding sites exit on the receptor [48,52], and displacement and cross-linking studies showed that other proteins may bind the YIGSR peptide [16]. A recent study in our laboratory focused on the role of the 67 kDa laminin receptor in laminin signaling, using cells expressing different levels of the receptor [32]. By stable transfection of A375SM melanoma cells, we established lines expressing reduced or elevated 67 kDa laminin receptor. The antisensetransfected cells that expressed reduced 67 kDa laminin receptor demonstrated significantly less aggressive tumor phenotype, as reflected by their reduced invasiveness through Matrigel, diminished attachment to laminin and decreased MMP-2 expression and activity [32]. We subsequently analyzed the involvement of the mitogen-activated protein kinases (MAPK) and dual specificity phosphatases (DUSP) in 67 kDa laminin receptor signaling [32]. MAPK are activated by phosphorylation of tyrosine and threonine in the activation loop and can be inactivated by serine/ threonine phosphatases, tyrosine phosphatases and DUSPs [33,71,72]. We found that the basal phosphorylation extent (activity) of ERK, JNK and p38 was significantly higher in cell lines expressing reduced 67 kDa laminin receptor, compared to parental cells and sense-transfected cells, regardless
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of the exposure to exogenous laminin-1. The addition of exogenous soluble laminin-1 resulted in an additional transient significant decrease in the phosphorylation of ERK, JNK and p38. This soluble laminin-induced dephosphorylation of all MAPK was independent of the 67 kDa laminin receptor level, since it was seen in all cell lines irrespective of the expression level of the receptor. These findings suggest that the 67 kDa laminin receptor induces prolonged dephosphorylation of ERK, JNK and p38, and that additional exogenous soluble laminin-1 induces further temporary dephosphorylation, apparently not via the 67 kDa laminin receptor. Further study focused on the DUSPs, MKP-1, PAC-1, MKP-4 and MKP-5, which were found to be expressed by the human A375SM melanoma cell line. We found that the increase in MAPK phosphorylation in cells expressing reduced 67 kDa laminin receptor is accompanied by a significant reduction in MKP-1 mRNA level and a significant increase in PAC-1 mRNA level, with no change in MKP-4 and MKP-5 mRNA levels [32]. Since prolonged activation of MAPK results in translocation of the activated kinases into the nucleus [33,71], and since MKP-1 and PAC-1 are nuclear enzymes that are regulated on the transcriptional level [71–74], it is reasonable to speculate that the increase that was seen in the phosphorylation of these MAPK in cells expressing reduced 67 kDa laminin receptor is related to decreased activity of MKP-1 [32]. The increase in PAC-1 mRNA level that accompanied the increase in the phosphorylation of ERK, JNK and p38 in cells expressing reduced 67 kDa laminin receptor can be explained as a negative feedback mechanism, since it has been shown that an increase in ERK phosphorylation results in transcription followed by increased activity of PAC-1, that in turn dephosphorylates and inactivates ERK [74,75]. In summary, the 67 kDa laminin receptor induces down-regulation of MKP-1 expression, that may contribute to the reduced activity (dephosphorylation) of MAPK induced by the receptor, that is followed by an upregulation of PAC-1 expression, as a negative feedback [32]. Interestingly, lower MAPK activity induced by the 67 kDa laminin receptor in our in vitro model, which was characteristic of aggressive phenotype of the tumor cells [32], correlates with our results in a study of clinical specimens from ovarian carcinoma patients.
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We found that increased level and activity of all three MAPK families in ovarian carcinoma cells in effusions is associated with clinical parameters of improved outcome and significantly longer overall survival [76]. 4.2. Integrins Integrins are a large family of cell receptors for extracellular matrix proteins and ligands on other cells (Table 2). Integrins are heterodimeric combination of various a-subunits with various b-subunits [2,39]. By having multiple integrins as receptors for common extracellular matrix proteins, cells have the flexibility to interact with different affinities at the same ligand site and at different sites within the same ligand. The ligand specificity for different integrins can be altered depending on the type of divalent cation present, the surrounding lipid environment and various cellspecific factors. Inside the cell, the short cytoplasmic domains of integrins associate with various cytoskeletal proteins that mediate integrin signal transduction [39]. At least eight integrins bind laminin; some of them bind additional extracellular matrix components as well, and cellular response depends on the sum of integrin–extracellular matrix interactions [2]. Integrins recognize mainly laminin a chains and hence determine cell adhesion and response to laminin isoforms. Although some functions may be common to all laminin variants, others may be unique and isoform-specific, depending on the tissue or organ in which they are abundant [5]. 4.2.1. Integrin signaling Although, it is clear that integrins transduce signals across the plasma membrane that affect gene expression, limited data exist regarding the specific signal transduction pathways activated by specific ligands [39,69]. There are two types of integrin-related signal transduction. The first is direct signaling, where stimulation of integrins by extracellular proteins triggers intracellular signaling events. The second is integrin modulation of mitogen signaling; in this case, integrin-mediated cell anchorage influences signaling pathways activated by growth factors [70]. In general, integrin direct signaling activates focal adhesion kinase (FAK), small GTPases of the Rho family,
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and MAPK [70,77,78], resulting in accumulation of highly phosphorylated proteins and cytoskeletal molecules at adhesion sites [79,80]. Integrin clustering causes activation and autophosphorylation of FAK, which is a cytoplasmic tyrosine kinase. Tyrosine-phosphorylated FAK can recruit Src-family kinases to focal contact sites. This sets up additional tyrosine phosphorylation of proteins such as cytoskeletal proteins and adaptor proteins such as Grb2 [70,78,81]. Small GTPases of the Rho family (Rho, Rac and Cdc42) are involved in integrin signal transduction and affect cytoskeleton arrangement. Rho contributes to cell adhesion to extracellular matrix. Rac and Cdc42, via phosphoinositide 3 kinase (PI3K), mediate the increase in cell motility and invasiveness induced by the integrin [82,83]. Some integrins activate MAPK cascades [80,84]. For example, laminin binding to the integrin a6b4 results in activation of an associated kinase and consequently tyrosine phosphorylation of the b4 subunit cytoplasmic domain, followed by association of the adaptor protein Shc with tyrosine phosphorylated b4 integrin subunit. Shc is then phosphorylated on tyrosine residues, presumably by an integrin-associated kinase, and combines with the adaptor protein Grb2, which exists in a complex with the ras GTP exchange factor SOS. This leads to Ras activation followed by activation of a kinase cascade consisting of Raf, MEK (MAPK/ERK kinase) and ERK, resulting in increased cell motility and proliferation [69,84]. In addition, integrin a6b4 activates the JNK cascade, via Rac1, resulting in jun protein expression. Jun associates with fos, whose expression is induced by ERK cascade, to form the AP-1 transcription factor [84]. In human hepatocellular carcinoma cells, laminin-binding integrin a6b1 stimulation resulted in FAK tyrosine phosphorylation, leading to FAK-GRB2 association and ERK cascade activation, which promotes tumor cell migration [85]. Interestingly, aggregation of integrin receptors, even in the absence of ligand occupancy, is sufficient to induce a prompt trans-membrane accumulation of at least 20 signal transduction molecules, including Src, Rho, Rac1, Ras, Erk1/2 and JNK. Thus, integrin aggregation with or without ligand occupancy triggers activation of both ERK and JNK cascades [80].
4.3. 67 kDa laminin receptor and integrins Integrins and the 67 kDa laminin receptor act together in transducing laminin effects. Limited data exist regarding the roles of the different receptors in mediating specific laminin effects. There are studies that indicate an association between the 67 kDa laminin receptor and the a6 integrin subunit, that is a part of the laminin-binding integrins a6b4 and a6b1 [21,23]. It was found that activation of human T lymphocytes induces an increase in both 67 kDa laminin receptor and a6b1 integrin expression, and that the two receptors mediate avid cellular adherence to laminin [52]. The 67 kDa laminin receptor and the a6b1 integrin were shown to be co-expressed and co-regulated in small-cell lung carcinoma cell lines, and their expression correlated with ability to adhere to laminin [86]. An additional study showed increased expression of the a6 integrin subunit and of the 67 kDa laminin receptor in pancreatic adenocarcinoma specimens, compared with normal pancreatic tissue from the same patient, indicating co-regulation of the receptors [87]. As opposed to the above report, differential expression of the a6 integrin subunit and the 67 kDa laminin receptor was seen in human hepatocellular carcinoma. Although higher expression of both the a6 integrin subunit and the 67 kDa laminin receptor was found in tumor specimens compared to normal tissues from the same patient, the increase in a6 integrin subunit expression was more pronounced than that of the 67 kDa laminin receptor, indicating different regulation of receptor expression [88]. An in vitro study found co-regulation and physical association of the a6 integrin subunit and the 67 kDa laminin receptor. Following incubation of a human vulvar epidermoid carcinoma cell line with laminin for different time periods, the regulation of the 67 kDa laminin receptor correlated with expression of the a6 integrin subunit but not with the expression of other laminin receptors, and cytokine treatment resulted in a reduction in the expression of these two receptors [24]. Specific reduction of the a6 integrin subunit by an antisense was accompanied by a proportional decrease in the cell surface expression of the 67 kDa laminin receptor. Biochemical analyses indicated co-immunoprecipitation of 67 kDa laminin receptor and a6 integrin subunit [24]. Integrins bind laminin at
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different sites than the 67 kDa laminin receptor, which may lead to higher laminin-binding affinity. Some investigators suggested that the 67 kDa laminin receptor is just a co-factor for laminin–integrin interactions [21,24,48], but other reports indicate that the 67 kDa laminin receptor may have additional functions [44,88]. The 67 kDa laminin receptor does not co-localize with a6 integrin subunit in neuroblastoma cell line [44]. Results from an in vitro study and analysis of clinical specimens in our laboratory are in agreement with the hypothesis that the 67 kDa laminin receptor is not merely a co-factor for laminin– integrin interactions. We found that A375SM melanoma cells express two alternatively spliced isoforms of the a6 integrin subunit, a6A and a6B. However, cells expressing reduced 67 kDa laminin receptor showed a significantly reduced mRNA level of the a6B integrin subunit isoform, with no significant change in a6A isoform mRNA level. Thus, the a6B is the important isoform in the concept of co-regulation with the 67 kDa laminin receptor in the A375SM melanoma cell line [32]. Our study of clinical material analyzed the expression of the 67 kDa laminin receptor and the a6 integrin subunit, in effusions and solid tumors of patients diagnosed with serous ovarian carcinoma, and analyzed their predictive roles. 67 kDa laminin receptor mRNA and protein expression was found to be independent of that of the a6 integrin subunit in both solid tumors and effusions of serous ovarian carcinoma. Expression of the 67 kDa laminin receptor was detected in the majority of specimens, at all anatomic sites, and did not correlate with clinico-pathological parameters or survival. In contrast, loss of a6 integrin subunit expression predicted better overall survival [89]. Malignant mesothelioma (MM) is one of the most aggressive human cancers, with a median survival of 8 months if untreated, and up to 2 years in recent series, when surgery was combined with adjuvant therapy [90]. With the exception of brain tumors, such as Glioblastoma Multiforme, that are confined to the central nervous system by anatomic structures, no tumor is less susceptible to clinically detectable distant metastasis and still is associated with these mortality figures. This despite the fact that MM is clearly capable of local invasion and displays the integrin profile needed in order to mediate attachment to all major extracellular matrix proteins [91,92].
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In a recent study, frequent mRNA, but only rare protein expression of the 67 kDa laminin receptor was seen in clinical specimens of MM (Reich et al., submitted for publication). In contrast, expression of this receptor was seen in the majority of breast and lung carcinomas, tumors with high metastatic potential, in addition to the above-described ovarian carcinomas (Reich et al., submitted for publication). These findings suggest that the differences between MM and carcinomas regarding expression of the 67 kDa laminin receptor may account at least in part for the reduced ability of MM to metastasize to distant organs, due to lack of the signaling mediated by the receptor. Local invasion and the less frequent distant metastasis in MM may be mediated by the a6 integrin laminin receptor rather than the non-integrin 67 kDa laminin receptor. Our recent finding that MM shows significantly higher expression of the a6 integrin subunit compared to ovarian and breast carcinomas using flow cytometry (Sigstad et al., submitted for publication) supports this hypothesis.
5. Summary The interaction of cancer cells with laminin is a key-event in tumor invasion and metastasis. Laminin effects are mediated by laminin receptors, and receptor expression is altered in cancer. Activation of a specific signal transduction pathway in the cell depends on the laminin isoforms the cell binds to, the conformation of the glycoprotein, the duration of exposure to laminin and the expression pattern of the different laminin receptors. All the above factors may be altered when normal tissue becomes neoplastic, resulting in various laminin mediated signaling that promote tumor dissemination.
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